Lookup NU author(s): Professor Tiago Outeiro
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Transcriptional dysregulation has been proposed to play amajor role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Fö rster Resonance Energy Transfer approaches. Htt-MeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD. © The Author 2013. Published by Oxford University Press. All rights reserved.
Author(s): McFarland KN, Huizenga MN, Darnell SB, Sangrey GR, Berezovska O, Cha J-HJ, Outeiro TF, Sadri-Vakili G
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Print publication date: 15/02/2014
Online publication date: 08/10/2013
Acceptance date: 03/10/2013
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
PubMed id: 24105466
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